1. Field of the Invention
The present invention relates to standardized solutions containing stabilizers and analytes adjusted to specific levels for calibration of chemical analyzers. In particular, this invention relates to an aqueous based stabilized standard solution for the calibration of clinical assays for assessing blood alcohol levels, total carbon dioxide, and ammonia.
2. Description of the Related Art
Generally, automated biochemical analyzers employ a combination of analyte specific chemical reagents and reaction monitoring means to assay or determine the presence or concentration of a specific substance or analyte within a liquid sample suspected of containing that particular analyte. Such analyzers are well known and almost universally employ some sort of a calibration curve to determine analyte concentration from the signal generated by the reaction monitoring means in response to the presence of the analyte.
It is regular practice within the biochemical analytical industry to establish a full calibration curve for a chemical analyzer by using multiple calibration solutions or calibrators which have been carefully prepared with known, predetermined concentrations of analyte. These calibration or standard solutions are assayed one or more times and the mean resulting reaction signals are plotted versus their respective known analyte concentrations. A continuous calibration curve is then produced using any of several mathematical techniques chosen to produce an accurate replication of the relationship between a reaction signal and the analyte concentration. The shape of the calibration curve is affected by a complex interaction between reagents, analyte and the analyzer's electromechanical design. Thus, even if the theoretical analyte-reagent reaction is known, it is generally necessary to employ mathematical techniques to obtain an acceptable calibration curve. For greatest accuracy, calibration curves are established at regular intervals, to compensate for reagent particulars, and on individual analyzers, to compensate for equipment performance. The range of analyte concentrations used in establishing a full calibration curve is typically chosen to extend below and beyond the range of analyte concentrations expected to be found within biological samples like blood, serum, plasma, urine and the like.
Since analytical clinical procedures are typically designed to analyze serum samples, calibration solutions may be formulated using a matrix that is identical to or bioactively equivalent to serum. Human serum has typically been used as starting material for calibration solutions; however, the techniques used for stripping away interfering chemicals often produce process artifacts and wide lot-to-lot variations making it difficult to manufacture these solutions reproducibly. An additional disadvantage of calibration solutions containing human serum is that they cannot be stored for longer periods since serum contains many labile components which negatively affect the stability of the product. For this reason calibration materials are often provided in a dry state (lyophilized); however, inaccurate re-hydration of these materials commonly leads to inaccurate calibration measures. For these reasons, it is highly advantageous that calibration solutions be prepared using an aqueous or buffered solution as a base matrix.
U.S. Pat. No. 3,960,497 discloses the basic concepts of calibrating and verifying the calibration of a chemical analyzer using standard solutions having known values of the particular characteristic being measured.
U.S. Pat. No. 4,843,013 discloses a synthetic liquid control standard comprising an aqueous solution and several hemoglobin fractions, and sodium, potassium, lithium and calcium salts.
U.S. Pat. No. 5,342,788 discloses a serum-free standard solution containing TBG, albumin, and buffer. When T4 or T3 is added to this solution, an equilibrium is established between bound and free hormone resembling that observed in human serum. Stability of the synthetic standard solution is said to be superior to a solution based in human serum and furthermore, bovine TBG afforded superior stability than TBG derived from human serum.
U.S. Pat. No. 5,518,929 discloses aqueous solutions containing buffers and electrolytes adjusted for the calibration and quality control of both blood gases such as carbon dioxide and oxygen, using ion selective electrodes.
U.S. Pat. No. 5,795,789 discloses a stabilized standard solution for the calibration of clinical assays useful in assessing thyroid function, including total thyroxine, unbound thyroxine, total triiodothyronine, unbound triiodothyronine, and thyroid stimulating hormone.
In order to extend the amount of time that a liquid calibration solution may be accurately used to calibrate an analyzer, stabilizers and preservatives are added to the solution to extend the use-life of a calibrator by reducing degradation of the analyte and ensuring against contaminants. Consequently, the requirements placed on a formulation chemist to produce a combination of matrix, analyte, stabilizers and preservatives that are compatible with the analytical system, which can contain the desired concentrations of all desired analytes, and at the same time are able to maintain stability are found to be quite restrictive. These requirements are particularly challenging in the instance that one analyte in a multi-analyte calibration solution is basic and another analyte is acidic. In such an instance, those skilled in the art have been taught that the basic and acidic analytes would quickly react with one another to form water and a salt and thus a calibrator containing basic and acidic analytes would be expected to have a very short use-life. As a result of such a teaching, at least two different calibration solutions have previously been required to support calibration protocols for the acidic analytes alcohol and total carbon or carbonate and for the basic analyte ammonia. This imposes undesirable production expenses by the manufacturer as well as increased purchasing and handling expenses by the clinical laboratory.
Accordingly, there remains a need for a single calibration solution containing known amounts of alcohol, carbonate and ammonia analytes so as to increase flexibility in use as well as reduce all around expenses. However, it is traditionally expected in the art that the combination of basic and acidic analytes would inherently and adversely affect the stability of the calibration solution. Carbonates in particular are known to be readily decomposed by acids. Normally, basic solutions require a pH range greater than about pH=8 to be stable and acidic solutions a pH range lower than about pH=5 to be stable. Notwithstanding the teachings of the art, it is an object of the present invention to provide a single, stabilized calibration solution having known amounts of acidic alcohol, acidic carbonate and basic ammonia so that the advantages of having a multi-analyte calibration solution may be realized over an extended period of time.